Abstract The primary goal of this research is to test the feasibility of using mouse models to examine the effect of congenital heart diseases (CHDs) on the onset and progression of Alzheimer?s disease (AD). CHDs are the most common structural birth defects, occurring in 1-5% of newborns. Owing to the greatly improved diagnostic and therapeutic strategies, ~90% of children with CHDs can now survive to adulthood. Adult CHD patients now outnumber pediatric CHD patients by a ratio of 2:1. A growing number of adult CHD patients are aging, posing new medical challenges in caring for these patients. A nationwide epidemiological study published in 2018 revealed that adults with CHDs have a significantly increased risk for developing AD compared to the general population, and that the risk is particularly increased for early onset of dementia. Therefore, the early abnormal heart development in embryos/neonates significantly increases the risk of later developing dementia/AD. The long interval between the occurrence of CHDs and the onset of AD makes studies of the CHD-AD interaction highly challenging. Thus, it is not entirely surprising that few, if any, such studies can be found in the literature. Considering that both CHDs and AD have been heavily studied through mouse genetics, we propose to develop mouse models to examine how CHDs affect AD. In our unpublished study, we used the cardiac troponin T (cTnt) ?Cre driver to specifically inactivate Sema6D in embryonic hearts. Mutant mice displayed the hypoplastic myocardial wall defect at P0 due to reduced cardiomyocyte proliferation. We plan to crossbreed Sema6D knockout mice with a well-established AD model line, APPNL-G-F/NL-G-F knock-in mice, to examine the impact of inborn cardiomyopathy on AD-like deficits in mice. Our central hypothesis is that congenital cardiomyopathy caused by embryonic heart deletion of Sema6D accelerates the onset and exacerbates the severity of AD-related deficits in AD mice. We will examine the cognitive and neuropathological defects in these mice in Aims 1 and 2, respectively. This project is highly innovative by nature. CHD is a newly identified risk factor for AD. Evaluating how CHDs impact AD is a completely new area for AD research. Our study represents the first to test the feasibility of using mouse models to study the CHD-AD interaction. Successfully accomplishing our research will open the door for future in vivo studies in this field.